1. Field of the Invention
The invention relates to diagnostic medical instruments and more particularly to apparatus for the collection and analysis of alveolar breath.
2. Brief Description of Related Art
Normal mammalian breath, including human alveolar breath contains a large number of volatile organic compounds in low concentrations (nanomolar or picomolar). Many of these compounds originate from the capillary blood; they enter the alveoli of the lungs by diffusion across the pulmonary alveolar membrane. Therefore, the analysis of breath opens a unique window onto the composition of the blood.
The collection and analysis of the breath presents several technical difficulties, but may yield information of considerable medical interest. There is evidence that the composition of alveolar breath may be altered in several disorders, including lung cancer, liver disease, inflammatory bowel disease, rheumatoid arthritis and schizophrenia. The chemical analysis of breath therefore provides a non-invasive diagnostic test for the diagnosis of these and other diseases.
The major technical difficulties in chemical analysis of breath arise from:
(1) the large numbers of volatile organic compounds (possibly 100 or more) found in breath and necessitating separation prior to assay (e.g.; by gas chromatography combined with mass spectroscopy) (GC/MS), and PA1 (2) the very low concentration of the compounds, which are below the limits of sensitivity of currently available GC/MS instruments, therefore necessitating concentration of the breath prior to analysis. PA1 (1) Subject comfort: the apparatus should present no significant resistance to exhalation (which might cause discomfort for the subject providing a breath sample). PA1 (2) Subject safety: the apparatus should provide no hazard to the subject, such as exposure to potential sources of inhaled infectious microorganisms. PA1 (3) Freedom from contamination: the apparatus should not incorporate any structural components such as plastics and adhesives containing volatile organic compounds which continuously outgas, causing contamination of the sample. PA1 (4) Alveolar sampling: normal mammalian breath contains two components: the "dead space" breath originating from the pharynx, trachea and bronchial tree where no gaseous interchange occurs, and alveolar breath from the alveoli of the lungs which contains the volatile organic compounds of interest which have diffused from the blood. The sample should be drawn principally from alveolar breath, not dead space breath. PA1 (5) Control of water condensation: Breath is saturated with water which condenses immediately onto cool surfaces in the breath collecting apparatus. This may result in partitioning of volatile organic compounds in the gaseous phase into the aqueous phase, with a consequent depletion of volatile organic compounds in the analyzed specimen. PA1 6. Concentration of sample: The ultimate purpose of the apparatus is to concentrate volatile organic compounds in the alveolar breath, while allowing the nitrogen, oxygen, and carbon dioxide in the breath to escape unhindered. The commonest concentration techniques are cryogenic (i.e.; capture in a cold trap), adsorptive (i.e.; capture in a trap containing an adsorptive resin or some other binding agent) or chemical (i.e.; capture by interaction with a chemical compound). PA1 (1) is transportable and operated by a technician or in portable embodiments of more complexity incorporates an arm containing the reservoir tube and the sampling tube; this arm can be swivelled at the end where it joins the device, in order to adjust to the height of the subject who is either seated or standing. The far end of this arm can be swivelled to accommodate the subject's mouth at a comfortable angle. PA1 (2) Incorporates a heating system, in both the arm and the central structure. The sampling tube and the reservoir tube are heated throughout their length, in order to prevent condensation of water and volatile organic compounds. PA1 (3) Eliminates the earlier need for supplying chemically purified air. Recent studies (unpublished) have shown that this procedure actually introduces impurities into the system, and yields inconsistent results with human subjects. With the subject breathing room air the results are more consistent and more easily interpreted than when chemically purified air is inspired. PA1 (4) Eliminates the provision for drawing the sample through a water trap. This procedure entails the risk of contamination of the specimen, as well as the possibility of losing water soluble volatile organic compounds from the breath sample. The heating system renders a water trap unnecessary, thereby resulting in a simpler, chemically cleaner, and more dependable apparatus. PA1 (5) Optionally eliminates provisions for a respirometer at the end of the reservoir tube. In practice, this was not found to be necessary. PA1 (6) Optionally eliminates a number of heavy and bulky components, to be smaller and portable. It can be manufactured as a hand-carried device which no longer needs to be wheeled about on a cart or can even be miniaturized to be hand supported in use. PA1 (7) May include provisions for alternative methods of collection of breath samples besides adsorptive trapping: i.e., cryogenic trapping, chemical trapping, evacuated container collections, and bag collections. It is considerably more versatile apparatus. PA1 A. a fluid reservoir container having PA1 B. valve means on the exit portal for controlled sealing and opening of the exit portal; PA1 C. means for maintaining said chamber at a temperature sufficient to prevent condensation of water and volatile compounds in the mammal's breath, associated with the reservoir container; PA1 D. means for sealed coupling of the reservoir container entry portal to the pulmonary airway of the mammal, whereby exhaled breath is directly delivered at full, undiluted concentration of compounds contained in the breath, to the reservoir container; PA1 E. a sample container for holding samples of the breath exhaled by the mammal into the reservoir container and selected for analysis to determine quantitative presence of those compounds of interest; PA1 F. valve means between the sampling portal of the reservoir container and the sample container for selectively directing breath samples from the reservoir container to the sample container; PA1 G. means for maintaining the selected breath at a temperature sufficient to prevent water condensation in the sample contained and the valve means for directing samples to the sample containers; and PA1 H. pump means for moving selected samples of the breath from the reservoir's container into the sample container.
The above-described difficulties may be circumvented by the use of a breath collecting apparatus which collects and concentrates the breath into a sample suitable for assay by GC/MS. However, the design and operation of an effective breath collecting apparatus presents a number of technical requirements:
Early apparatus for the collection and analysis of alveolar breath was described by us in an article published in Clin. Chem., 38/1, 60-65 (1992). The state of the art was also described by us in Scientific American, Vol. 267, No. 1, July 1992, pps. 74-79. Although the apparatus of the present invention is superficially similar to the apparatus previously described by us, it contains a number of improvements which have resulted in functional advantages not previously enjoyed. For example, embodiment apparatus of the present invention: